Agents designed to selectively inhibit the replication of a rapidly growing pathogen or cancer inevitably face a challenge from the development of drug-resistance. This problem is viewed by many clinicians as one of the major impediments to the effective management of malignant disease or the control of infectious agents which undergo major genetic variation. A related dilemma is presented by autoimmune disease, where a disease-causing cell population may be heterogeneous with respect to marker antigens which could be targeted as part of a therapeutic strategy.
The challenge of genetic variation to disease therapy is well illustrated by the problem of antiviral drug-resistance, though a similar situation holds true for resistance to anti-microbials and chemotherapeutics. The clinical emergence of drug-resistant virus has been documented in most instances in which antiviral therapy has been applied, including HIV, herpes simplex virus, varicella zoster virus, cytomegalovirus, influenza A virus, and rhinovirus (Richman, Curr. Opin. Infect. Dis. 3:819-823 (1990)). HIV infection provides a clear example of this problem, given its chronic, persistent nature, the high rate of viral replication, and the error-prone character of reverse transcriptase (RT). Resistance has been observed for every HIV antiviral tested, including nucleoside analogs (AZT, ddI, ddC, d4T and TSAO), non-nucleoside RT inhibitors (Merck's L-697,639 and Boehringer Ingelheim's nevirapine), and a protease inhibitor (Richman, Annu. Rev. Pharmacol. Toxicol. 32:149-164 (1993)).
The clinical significance of drug-resistance in HIV infection is best documented for AZT. While AZT reduced the rate of mortality in AIDS patients by over half during the first 12 months of treatment, ongoing therapy out to 24 months did not provide any additional advantage to the treated group. The apparent loss of AZT clinical efficacy correlates with the finding that by 12 months of therapy, approximately 90% of individuals with late-stage disease have developed AZT resistant virus (Richman et al., J. AIDS 3:743-746 (1990)). Similarly, the loss of antiviral activity observed with the non-nucleoside RT inhibitors within two months of their administration is associated with the rapid appearance of drug-resistant virus (Nunberg et al., J. Virol., 65:4887-4892 (1991); Richman et al., Proc. Natl. Acad. Sci., 88:11241-11245 (1991)).
Thus, while antiviral therapy with single agents can be quite effective for short periods, extended treatment of chronic or latent infections like HIV and the herpes viruses may require the application of combination therapies. Such a strategy is, however, often impractical due to the additional problems of cross-resistance as well as the cumulative side-effects of multiple agents. It is therefore desirable to design an therapeutic agent which can attack the pathogen at multiple points, in a fashion that minimizes cross-resistance, and has the safety profile of a single active agent. The present invention achieves this goal by providing multispecific chimeric receptors.